ABSTRACT
A new synthesis of LYS228, fitting for further process development for commercial manufacture, is described. The key features of this synthesis include development of new protocols for acylation reactions, application of an asymmetric hydrogenation via dynamic kinetic resolution, and a late-stage ring closure to form ß-lactam 1.
Subject(s)
Anti-Bacterial Agents , Monobactams , Hydrogenation , Stereoisomerism , beta-LactamsABSTRACT
Synthetic modification of cyclosporin A at P3-P4 positions led to the discovery of NIM258, a next generation cyclophilin inhibitor with excellent anti-hepatitis C virus potency, with decreased transporter inhibition, and pharmacokinetics suitable for coadministration with other drugs. Herein is disclosed the evolution of the synthetic strategy to from the original medicinal chemistry route, designed for late diversification, to a convergent and robust development synthesis. The chiral centers in the P4 fragment were constructed by an asymmetric chelated Claisen rearrangement in the presence of quinidine as the chiral ligand. Identification of advanced crystalline intermediates enabled practical supply of key intermediates. Finally, macrocyclization was carried out at 10% weight concentration by a general and unconventional "slow release" concept.
Subject(s)
Antiviral Agents/chemistry , Cyclosporine/chemistry , Hepacivirus/physiology , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Cyclization , Cyclosporine/chemical synthesis , Cyclosporine/pharmacology , Dipeptides/chemical synthesis , Dipeptides/chemistry , Drug Design , Quinidine/chemistry , Stereoisomerism , Virus Replication/drug effectsABSTRACT
A practical synthetic strategy to a chiral azabicycclooctanyl derivative (1), a potent DPP-4 inhibitor, starting from a commercially available nortropine is described. The stereogenic center of 1 was established employing a modified protocol of Ellman's diastereoselective addition of a benzylic nucleophile to tert-butanesulfinimine. Other key steps include Corey-Chaykovsky reaction, Meinwald rearrangement, and CDMT-promoted amide bond formation involving a sterically hindered amine 2.
